Nicotinic acid esters and pharmaceutical compositions containing them

ABSTRACT

PCT No. PCT/GB96/01054 Sec. 371 Date Mar. 3, 1998 Sec. 102(e) Date Mar. 3, 1998 PCT Filed May 1, 1996 PCT Pub. No. WO96/34858 PCT Pub. Date Nov. 7, 1996Compounds, compositions, and methods of use as a pharmaceutical, where the compounds have structure (I), where B is -C(=O)- or -CH2-O-, C is a direct bond or is a diol residue, a hydroxy-substituted carboxylic acid residue, or a dicarboxylic acid residue, and D is a fatty acid residue or a fatty alcohol residue, where the acid residues or alcohol residues for ester linkages with the corresponding alcohols or acids.

This application is a 371 of PCT/GB96/01054 filed May 1, 1996.

FIELD OF THE INVENTION

The invention relates to new esters and to compositions forpharmaceutical uses, particularly for managing cardiovascular diseases,inflammatory diseases, dermatological disorders including baldness,diabetes, cancer, psychiatric disorders and other appropriate medicaland nutritional disorders.

BACKGROUND Blood Cholesterol

There is considerable background in relation to the specific matter ofblood cholesterol levels. As discussed in EPA 0 087 864, essential fattyacids (EFAs), particularly gammalinolenic acid (GLA) anddihomogammalinolenic acid (DGLA), act to lower blood cholesterol levels,the mechanism being unknown; these acids of course are the startingmaterials for 1-series PG synthesis, the bodily conversions of EFAsgenerally being as set out in Table 1 below:

                  TABLE 1                                                         ______________________________________                                        n-6 EFA's               n-3 EFA's                                             ______________________________________                                        18:2n-6                 18:3n-3                                               (Linoleic acid, LA)     (α-Linolenic acid, ALA)                         ↓     δ-6-desaturase                                                                     ↓                                              18:3n-6                 18:4n-3                                               (γ-Linolenic acid, GLA)                                                                         (Stearidonic acid, SA)                                ↓     elongation ↓                                              20:3n-6                 20:4n-3                                               (Dihomo-γ-linolenic                                                     acid, DGLA)                                                                   ↓     δ-5-desaturase                                                                     ↓                                              20:4n-6                 20:5n-6                                               (Arachidonic acid, AA)  (Eicosapentaenoic acid, EPA)                          ↓     elongation ↓                                              22:4n-6                 22:5n-3                                               (Adrenic acid)                                                                ↓     δ-4-desaturase                                                                     ↓                                              22:5n-6                 22:6n-3                                                                       (Docosahexaenoic acid, DHA)                           ______________________________________                                    

The acids, which in nature are of the all-cis configuration, aresystematically named as derivatives of the corresponding octadecanoic,eicosanoic or docosanoic acids, e.g. z,z-octadeca-9,12-dienoic acid orz,z,z,z,z,z-docosa-4,7,10,13,16,19-hexaenoic acid, but numericaldesignations based on the number of carbon atoms, the number of centresof unsaturation and the number of carbon atoms from the end of the chainto where the unsaturation begins, such as, correspondingly, 18:2n-6 or22:6n-3 are convenient. Initials, e.g., EPA and shortened forms of thename e.g. eicosapentaenoic acid are used as trivial names in some of thecases.

As also discussed in EPA 0 087 864, there are a number of agents whichlower cholesterol levels in the blood by binding to bile salts in thegastro-intestinal tract and directly enhancing cholesterol excretion inthe faeces. Illingworth et al in the Lancet for Feb. 7, 1981 pp 296-7report use of the bile salt binder colestipol, plus nicotinic acid(niacin) against an inherited high blood-cholesterol condition, with"dramatic" effect. No mechanism is discussed, the article suggestingsimply that therapy, in addition to taking binders, may best be directedtowards reducing lipoprotein synthesis, and saying that niacin has beenreported to do that.

Niacin is one of the two forms of Vitamin B3, the other beingniacinamide; by an unknown mechanism it acts systematically to lowercholesterol levels in blood without any substantial effect oncholesterol excretion.

The effect of niacin is believed to be due to an effect it has instimulating prostaglandin (PG) synthesis, specifically PGE₁ synthesisfrom dihomogammalinolenic acid and PGD₂ synthesis from arachidonic acid,as part of a mechanism that leads to reduced cholesterol synthesis andhence reduced levels in the blood. It is for example known that PGE₁stimulates the formation of cyclic AMP (adenosine monophosphate) andthat cyclic AMP inhibits cholesterol synthesis. Further, niacin, inaddition to its blood cholesterol lowering effect, causes flushing andtingling, effects that the inventor has noted are also among those ofstimulating prostaglandin synthesis, particularly PGE₁ and PGD₂synthesis.

Niacinamide, in contrast, though generally equivalent in its bodilyeffects to niacin, does not show this stimulating effect on PGsynthesis, nor does it cause flushing and tingling or show a bloodcholesterol lowering effect. Linkage of these facts as instances of theunusual existence of differences in properties between niacin andniacinamide, supports the view that PG levels and blood cholesterollevels are linked.

BACKGROUND Microcirculation

More recently, and quite separately from questions of blood cholesterollevel, it has become apparent that many disease states may involvepartial reductions in blood flow in the micro circulation. Such reducedmicrocirculatory flow has been reported or presumed to be important indiabetes, in cardiovascular diseases, in inflammatory diseases, indermatological disorders including baldness, in cancer and in variousother disorders. Particularly in cancer, partial or complete shutdown ofthe capillary bed may be important in preventing expected responses totreatment using such agents as radiation, chemotherapy or photodynamictherapy. The effects of niacin and fatty acids, especially EFAs, on themicrocirculation are to maintain normal capillary flow, partly byunknown mechanisms and partly by the stimulation of the formation ofvasodilator substances such as prostaglandins E₁ and D₂ and nitricoxide. The EFAs themselves, particularly GLA, DGLA and EPA and DHA arealso of value in reducing damage to normal tissues during radiotherapyas described in patents EP-A-0,416,855 and EP-A-0,609,064. Thusniacin-EFA derivatives of the types discussed hereinafter are ofparticular value in association with radiotherapy because they mayenhance the damaging effects of radiation on the tumour while at thesame time reducing the damaging effects on normal tissues. Manychemotherapeutic agents used in cancer also cause severe side effectsand the niacin-EFA derivatives may be used in managing these also.

THE INVENTION

The invention concerns niacin compounds both as such when new, and inrelation to the indications discussed above, in respect of which itproposes administration of niacin as the compounds.

Such administered compound may be an ester: ##STR1## where R is a fattyacid alcohol chain --CH₂ --R¹, R¹ being the carbon chain of an n-6 orn-3 essential or other C₁₂ or longer chain fatty acid R¹ COOH,particularly GLA, DGLA or AA of the n-6 series, or EPA or DHA of the n-3series.

Other directly linked compounds of value are esters of niacin alcohol(3-pyridyl carbinol) with the fatty acids, niacin alcohol beingconsidered herein as included within the broad term niacin.

The invention extends further to esters of niacin with "extended" fattyacids where a fatty acid forms a monoester of a diol and the otherhydroxy function of the diol is esterified to the niacin (alternativelya niacin monoester of the diol may be formed and then reacted with thefatty acid). In such `extended` esters R in the formula above is:##STR2## where R¹ is as before and A is a diol residue.

Three other classes of "extended" compounds are, for example, possible:

(i) niacin and fatty acid alcohol linked through a hydroxycarboxylicacid residue.

(ii) niacin alcohol and fatty acid linked through a hydroxycarboxylicacid residue.

(iii) niacin alcohol and fatty alcohol linked through a dicarboxylicacid residue.

The general formula is then: ##STR3## where B is --C(═O)-- (nicotinicacid) or --CH₂ --O-- (niacin alcohol), C which is optional is a diol orhydroxy carboxylic acid or dicarboxylic acid residue, and D is a fattyacid or fatty acid alcohol residue, the links between B and C and C andD being ester links.

A particularly suitable diol is 1,3-dihydroxy propane (2-deoxyglycerol), well tolerated in the body, but broadly a diol or other"link" may be any pharmacologically acceptable compound giving suitablepharmacokinetics in the ester, including release of the niacin and fattyacid in the body, and desirably non-chiral. A diol may thus have acyclic or non-cyclic structure, with or without hetero-atoms andsaturated or unsaturated, but especially a hydrocarbon structure--(CH)_(n) -- where n=1 to 10. The corresponding use of1-carboxy-3-hydroxypropane or 1,3-dicarboxypropane (malonic acid) orcorresponding compounds to form the extended molecules in classes(i)-(iii) is appropriate.

All of the compounds discussed contain one or more ester linkages. Thepreparation of these compounds may be achieved by any reasonable methodof ester synthesis and especially:

(i) by reaction of an alcohol with the acid chloride, acid anhydride orother suitable acid derivative with or without the presence of anorganic tertiary base, e.g. pyridine, in a suitable inert solvent, e.g.methylene chloride, and at a temperature between 0° C. and 120° C.

(ii) by reaction of an alcohol with the acid or a short or medium chainlength ester of the acid, in the presence of a suitable acid catalyst,e.g. p-toluenesulphonic acid, with or without a suitable inert solvent,e.g. toluene, at a temperature between 50° C. and 180° C. such that thewater or alcohol formed in the reaction is removed, e.g. by azeotropy orunder vacuum.

(iii) by reaction of an alcohol with the acid in the presence of acondensing agent, e.g. 1,3-dicyclohexylcarbodiimide with or without asuitable base, e.g. 4-(N,N-dimethylamino)pyridine, in an inert solvent,e.g. methylene chloride, at a temperature between 0° C. and 50° C.

(iv) by reaction of an alcohol with the acid or a short or medium chainlength ester of the acid, or an activated ester thereof, e.g. vinyl,trifluoroethyl, in the presence of a hydrolase enzyme, e.g. hog liveresterase, with or without a suitable solvent, e.g. hexane attemperatures between 20° C. and 80° C. under conditions such that thewater or alcohol by-product formed in the reaction is removed from thereaction mixture, e.g. molecular sieves, vacuum.

(v) by reaction of the acid with a suitable alcohol derivative, e.g.tosylate, iodide, with or without the presence of a suitable base, e.g.potassium carbonate, in a suitable inert solvent, e.g.dimethylformamide, and at a temperature between 0° C. and 180° C.

(vi) by reaction of an acid ester (acid-CO₂ Y) with the alcohol in thepresence of a catalytic amount of an alkoxide of type M⁺ OY⁻ where M isan alkali or alkaline earth metal, e.g. sodium, and Y is an alkyl groupcontaining 1-4 carbon atoms which may be branched, unbranched, saturatedor unsaturated. The reaction is carried out with or without a suitablesolvent, e.g. toluene, at temperatures between 50° C. and 180° C. suchthat the lower alcohol, HOY, is removed from the reaction mixture, e.g.by azeotropy or vacuum.

The value of the esters and other derivatives is believed to be inbringing the niacin and essential fatty acid (or alcohol) to beartogether, or possibly in enhancing transport of the niacin in the bodyby virtue of the lipophilic fatty acid carbon chain or "tail". In thelatter case, the fatty acid can be other than GLA, DGLA or AA or theother specified acids, which themselves can be taken separately or usedas a vehicle for the niacin ester.

In pharmaceutical terms there is a particular value in combining twoactive ingredients within a single molecule. With a mixture of twoactive ingredients directed at a particular clinical indication,regulatory authorities would normally require trials of placebo comparedto each active ingredient separately as well as the two together. Whenthe two actives are part of a single molecule, the actives will notusually have to be tested separately, so greatly reducing the complexityand cost of clinical trials. Thus irrespective of any synergisticinteractions there is pharmaceutical value in combining niacin with oneof the fatty acids in a single molecule. Many of the compounds arehowever to our knowledge novel and are claimed as such, irrespective oftheir particular use.

Dose Ranges

Suitable amounts of active materials are:

Niacin compound, (calculated as niacin): 10 mg-20 g, preferably 0.5 g to10 g and very preferably 1 to 5 g daily;

together with the corresponding amount of fatty acid or fatty acidalcohol required by the stoichiometry of the compound.

Pharmaceutical Presentation

The compositions according to the invention are conveniently in a formsuitable for oral, rectal, parenteral or topical administration in asuitable pharmaceutical vehicle, as well known generally for anyparticular kind of preparation.

Advantageously a preservative is incorporated into the preparations e.g.alpha-tocopherol in a concentration of about 0.1% by weight has beenfound suitable for the purpose. Alternatively, the materials of Europeanpatent application EP-A-0 577 305 may be used.

The niacin esters are liquid at normal temperatures and may be presentedas such or with other oily carriers or diluents in any appropriate form.Such forms would include soft or hard gelatin capsules, tabletted dryforms, emulsions, liposomes, liquids, enteral or parenteral preparationsor any other form known to those skilled in the art.

As one specific example, four soft gelatin capsules containing niacin asits ester with GLA alcohol, 0.5 g, may be administered thrice daily inthe treatment of any appropriate disease and in particular the diseasesmentioned earlier. Alternatively the same material may be presented asan emulsion, for example, using phospholipids or galactolipids asemulsifiers, or as a topical product containing 0.01% to 20% of theniacin ester. Any of the other compounds noted may be presented insimilar ways using techniques known to those skilled in the art.

SYNTHESIS

The following examples illustrate the invention.

EXAMPLE 1 z,z,z-octadeca-6,9,12-trienyl nicotinate Ester of Niacin andGLA Alcohol

1,3-Dicyclohexylcarbodiimide (97 g, 0.49 mol) and4-(N,N-dimethylamino)pyridine (65 g, 0.53 mol) in methylene chloride(800 ml) were added with stirring to a solution of nicotinic acid (60 g,0.49 mol) and z,z,z-octadeca-6,9,12-trienol (107 g, 0.41 mol) inmethylene chloride (1200 ml). The progress of the reaction was monitoredby tlc. On completion, the reaction mixture was filtered and the organiclayer washed with 2M hydrochloric acid (500 ml) and water (3×500 ml),dried with magnesium sulphate and concentrated under reduced pressure.Purification by dry column chromatography using a gradient of ethylacetate in hexane yielded z,z,z-octadeca-6,9,12-trienyl nicotinate as apale yellow oil in 91% yield.

EXAMPLE 2 z,z,z-eicosa-8,11,14-trienyl nicotinate Ester of Niacin andDGLA Alcohol

Prepared as in the above method but replacingz,z,z-octadeca-6,9,12-trienol with z,z,z-eicosa-8,11,14-trienol. Theproduct was obtained as a pale yellow oil in 79% yield.

EXAMPLE 3 1-(z,z,z-octadeca-6,9,12-trienoyloxy)-3-(nicotinyloxy)-propaneC₃ -linked Diester of Niacin and GLA

1,3-Dicyclohexylcarbodiimide (211 g, 1.02 mol) and4-(N,N-dimethylaminopyridine (141 g, 1.15 mol) in methylene chloride(2000 ml) were added with stirring to a solution of nicotinic acid (131g, 1.07 mol) and 1-(z,z,z-octadeca-6,9,12-trienyloxy)-3-hydroxypropane(300 g, 0.89 mol) in methylene chloride (2000 ml). The progress ofreaction was monitored by tlc. On completion, the reaction mixture wasfiltered and the organic layer washed with 2M hydrochloric acid (2000ml) and water (3×2000 ml), dried with magnesium sulphate andconcentrated under reduced pressure. Purification by dry columnchromatography using a gradient of ethyl acetate in hexane yielded1-(z,z,z-octadeca-6,9,12-trienoyloxy)-3-(nicotinyloxy)-propane as a paleyellow oil in 81% yield.

To prepare the 1-(z,z,z-octadeca-6,9,12-trienoyloxy)-3-hydroxypropaneused, a solution of z,z,z-octadeca-6,9,12-trienoic acid (150 g) inmethylene chloride (500 ml) was added dropwise to a mixture of1,3-dihydroxypropane (205 g), 1,3-dicyclohexylcarbodiimide (130 g) and4-(N,N-dimethylamino)pyridine (87 g) in methylene chloride (2500 ml) atroom temperature under nitrogen. When tlc indicated that the reactionhad gone to completion, the reaction mixture was filtered. The filtratewas washed with dilute hydrochloric acid, water and saturated sodiumchloride solution. The solution was dried, concentrated and purified bydry column chromatography to yield1-(z,z,z-octadeca-6,9,12-trienoyloxy)-3-hydroxypropane as a pale yellowoil.

EXAMPLE 4 (3-Pyridyl)methyl-(z,z,z-octadeca-6,9,12-trienoate) Ester ofNiacin Alcohol and GLA

A mixture of 1,3-dicyclohexylcarbodiimide (33.55 g, 0.1623 mol),4-(N,N-dimethylamino)pyridine (19.87 g, 0.1626 mol),z,z,z-octadeca-6,9,12-trienoic acid (37.67 g, 0.1355 mol) and 3-pyridylcarbinol (17.70 g, 0.1622 mol) were stirred as a solution in methylenechloride (1 liter) under a nitrogen atmosphere at room temperature. Theprogress of the reaction was followed by t.l.c. On completion, thereaction mixture was filtered and the organic layer washed with 2M HCl(1 liter), water (1 liter), saturated sodium bicarbonate solution (1liter) and water (2×1 liter). The organic layer was dried over anhydroussodium sulphate, filtered and stripped to dryness under reducedpressure. Purification by flash chromatography (ethyl acetate/hexane)yielded the title compound as a clear, pale yellow oil.

EXAMPLE 5 (z,z,z-octadeca-6,9,12-trienoyloxy)(3-nicotinyloxy)methane C₁Linked Diester of Niacin and GLA

Part 1: Chloro(z,z,z-octadeca-6,9,12-trienoyloxy)methane

Anhydrous zinc chloride (88 mg) was added to a mixture ofz,z,z-octadeca-6,9,12-trienoyl chloride (34.7 mmol) and paraformaldehyde(34.7 mmol). The mixture was stirred under an atmosphere of nitrogen atroom temperature for 30 minutes. The reaction was then equipped with areflux condenser and calcium chloride drying tube and heated at 90° C.for 6 hours. After completion of the reaction as shown by tlc, themixture was diluted with hexane and purified by flash chromatography togive chloro-(z,z,z-octadeca-6,9,12-trienoyloxy)methane as a clear oil.

Part 2: (z,z,z-octadeca-6,9,12-trienoyloxy)(3-nicotinyloxy)methane

To a solution of niacin (0.306 mmol) in 400 μl of dry pyridine withstirring in an atmosphere of nitrogen was addedchloro(z,z,z-octadeca-6,9,12-trienoyloxy)methane (0.306 mmol) andtriethylamine (0.303 mmol). The mixture was heated at 80° C. for 5 hoursafter which tlc indicated the reaction had gone to completion. Thepyridine was evaporated and the residue dissolved in chloroform, washedwith water, dried, concentrated and purified by flash columnchromatography to give(z,z,z-octadeca-6,9,12-trienoyloxy)(3-nicotinyloxy)methane as a clearoil.

EXAMPLE 6(z,z,z,z,z-eicosa-5,8,11,14,17-pentaenoyloxy)(3-nicotinyloxy)methane C₁Linked Diester of Niacin and EPA

Part 1: chloro(z,z,z,z,z-eicosa-5,8,11,14,17-pentaenoyloxy)methane

z,z,z,z,z-eicosa-5,8,11,14,17-pentaenoyl chloride (28 mmol) was reactedwith paraformaldehyde (28 mmol) under the same conditions as given inExample 5, Part 1 to givechloro(z,z,z,z,z-eicosa-5,8,11,14,17-pentaenoyloxy)methane as a clearoil.

Part 2:(z,z,z,z,z-eicosa-5,8,11,14,17-pentaenoyloxy)(3-niconinyloxy)methane

Niacin (0.286 mmol) was reacted withchloro(z,z,z,z,z-eicosa-5,8,11,14,17-pentaenoyloxy)methane (0.286 mmol)under the same conditions as Example 5, Part 2 to give(z,z,z,z,z-eicosa-5,8,11,14,17-pentaenoyloxy)(3-nicotinyloxy)methane asa clear oil.

EXAMPLE 7(±)-1-(z,z,z,-octadeca-6,9,12-trienoyloxy)-1-(3-nicotinyloxy)ethane C₁,(Methyl Substituted) Linked Diester of Niacin and GLA

Part 1: (±)-1-chloro-1-(z,z,z-octadeca-6,9,12-trienoyloxy)ethane

Anhydrous zinc chloride (300 mg) was added toz,z,z-octadeca-6,9,12-trienoyl chloride (120 mmol). Acetaldehyde (120mmol) was added dropwise with stirring over 30 minutes in an ice bathunder an atmosphere of nitrogen. The reaction mixture was then stirredat room temperature for an additional 40 minutes and was shown to becomplete by tlc. Water was added and the mixture was extracted twicewith diethyl ether. After drying the solvent was evaporated to give(±)-1-chloro-1-(z,z,z-octadeca-6,9,12-trienoyloxy)ethane as a clear oil.

Part 2:(±)-1-(z,z,z-octadeca-6,9,12-trienoyloxy)-1-(3-nicotinyloxy)ethane

To a solution of niacin (29 mmol) in 30 ml of dry pyridine with stirringin an atmosphere of nitrogen was added(±)-1-chloro-1-(z,z,z-octadeca-6,9,12-trienoyloxy)ethane (29 mmol) andtriethylamine (29 mmol). The mixture was heated at 80° C. for 5 hoursafter which time tlc indicated the reaction had gone to completion. Thepyridine was evaporated and the residue dissolved in chloroform, washedwith water, dried, concentrated and purified by flash columnchromatography to give(±)-1-(z,z,z-octadeca-6,9,12-trienoyloxy)-1-(3-nicotinyloxy)ethane as aclear oil.

EXAMPLE 8 (3-pyridyl)methyl-(z,z,z-octadeca-6,9,12-trienyl)-succinateDiester of Niacin Alcohol and GLA Alcohol with Succinic Acid

Part 1: z,z,z-octadeca-6,9,12-trienyl succinate (ester of GLA alcoholand succinic acid).

A solution of z,z,z-octadeca-6,9,12-trienol (2 g, 7.56 mmol) andsuccinic anhydride (757 mg, 7.56 mmol) in tetrahydrofuran (40 ml) wasprepared at room temperature and cooled to 0° C. To this was addeddropwise with stirring a solution of DBU (1.15 g, 7.56 mmol) intetrahydrofuran (20 ml) under an atmosphere of nitrogen. On completionof the reaction as shown by tlc, the mixture was diluted with diethylether (100 ml), washed with 2M hydrochloric acid (2×100 ml), water(2×100 ml) and saturated sodium chloride solution (2×100). The organicphase was dried with magnesium sulfate, filtered and concentrated underreduced pressure to yield z,z,z-octadeca-6,9,12-trienyl succinate as apale yellow oil.

Part 2: (3-pyridyl)methyl-(z,z,z-octadeca-6,9,12-trienyl)-succinate(diester of niacin alcohol and GLA alcohol with succinic acid).

z,z,z-octadeca-6,9,12-trienyl succinate (1.50 g, 4.11 mmol) in methylenechloride (10 ml) was added dropwise with stirring to a solution of3-pyridylcarbinol (0.45 g, 4.11 mmol), 1,3-dicyclohexylcarbodiimide(0.93 g, 4.53 mmol) and 4-(N,N-dimethylamino)pyridine (0.65 g, 5.35mmol) in methylene chloride (10 ml) at room temperature under anatmosphere of nitrogen. On completion of the reaction as shown by tlc,the mixture was filtered, concentrated under reduced pressure andpurified by flash column chromatography (chloroform) to yield(3-pyridyl)methyl-(z,z,z-octadeca-6,9,12-trienyl)-succinate as a paleyellow oil.

EXAMPLE 9 z,z,z-octadeca-6,9,12-trienyl-(2-nicotinyloxy)acetate Diesterof Nicotinic Acid and GLA Alcohol with Glycolic Acid

Part 1: z,z,z-octadeca-6,9,12-trienyl-(2-chloro)acetate (chloroacetylester of GLA alcohol).

To an ice-cooled solution of z,z,z-octadeca-6,9,12-trienol (2 g, 7.56mmol) and triethylamine (2.02 g, 20 mmol) in methylene chloride (20 ml)was added dropwise with stirring chloroacetyl chloride (1.13 g, 10 mmol)in methylene chloride (20 ml) under an atmosphere of nitrogen. Oncompletion of the reaction as shown by tlc, the mixture was washed withwater (2×100 ml) and saturated sodium chloride solution (100 ml). Theorganic phase was dried with magnesium sulfate, filtered andconcentrated under reduced pressure. Toluene (100 ml) was added toazeotropically remove final traces of water.z,z,z-octadeca-6,9,12-trienyl-(2-chloro)acetate was obtained as a darkbrown oil.

Part 2: cesium nicotinate (cesium salt of nicotinic acid).

Nicotinic acid (0.86 g, 7 mmol) and cesium carbonate (1.14 g, 3.5 mmol)were swirled in methanol (60 ml) until a clear solution resulted.Methanol was removed in vacuo to yield cesium nicotinate as a whitesolid.

Part 3: z,z,z-octadeca-6,9,12-trienyl-(2-nicotinyloxy)acetate (diesterof nicotinic acid and GLA alcohol with glycolic acid).

Cesium nicotinate (1.79 g, 7 mmol) andz,z,z-octadeca-6,9,12-trienyl-(2-chloro)acetate (2.39 g, 7 mmol) werestirred overnight at room temperature in anhydrous N,N-dimethylformamide(70 ml) under an atmosphere of nitrogen. On completion of the reactionas shown by tlc, the mixture was partitioned between hexane (160 ml) andsaturated sodium chloride solution (200 ml). The aqueous phase was backextracted with hexane (160 ml) and the combined hexane layers werewashed with saturated sodium chloride solution (200 ml). The organicphase was dried with magnesium sulfate and concentrated under reducedpressure to yield z,z,z-octadeca-6,9,12-trienyl-(2-nicotinyloxy)acetateas a brown oil.

We claim:
 1. A compound of the structure: ##STR4## wherein B is selectedfrom the group consisting of --C(═O)-- and --CH₂ --O--, C is selectedfrom the group consisting of a diol residue a hydroxy-substitutedcarboxylic acid residue and a dicarboxylic acid residue, with theproviso that when B is --CH₂ --O--, C is not a diol residue, D isselected from the group consisting of a fatty acid residue and a fattyalcohol residue, wherein the acid residues or alcohol residues formester linkages with the corresponding alcohols or acids.
 2. A compoundaccording to claim 1, wherein the fatty acid or fatty acid alcoholresidue is a residue of an n-6 or n-3 essential or other C₁₂ or longerchain fatty acid.
 3. A compound according to claim 1, wherein C has one,two or three carbon atoms.
 4. A compound according to claim 2, whereinthe fatty acid or fatty acid alcohol residue is GLA, DGLA, or AA of then-6 series or is EPA or DHA of the n-3 series.
 5. A pharmaceuticalcomposition comprising one or more compounds of claim 1, 2, or 3, and apharmaceutically acceptable carrier.
 6. A nutritional or skin carecomposition for oral, parenteral, or topical administration, comprisingone or more compounds of claim 1, 2, or 3, together with a suitablepharmaceutically acceptable carrier.
 7. A method of managingcardiovascular diseases, inflammatory diseases, dermatological disordersincluding baldness, diabetes, cancer, psychiatric disorders and otherappropriate medical and nutritional disorders comprising administeringto a patient in need thereof an effective amount of the compoundaccording to claim 1, 2 or
 3. 8. A method for the management ofradiotherapy for cancer, or of chemotherapy for cancer comprisingadministering to a patient in need thereof an effective amount of thecompound according to claim 1, 2, or 3.